Survivin represents one of the most tumor-specific genes in the human genome according to comparisons of the transcriptomes of normal and malignant cells (Velculescu, V. E. et al. 1999 Nature Gen 23:387-388). The 17 kDa protein Survivin is scarcely expressed in normal adult tissues, but is found at high levels in most human cancers (Ambrosini, G. et al. 1997 Nature Med 3:917-921). Normally, Survivin is expressed only during late stages of the cell cycle (particularly mitosis and anaphase), where it associates with the mitotic spindle and related structures, performing functions important for chromosome segregation and cytokinesis (Li, F. et al. 1998 Nature 396:580-587; Reed, J. C. & Bischoff, J. R. 2000 Cell 102:545-548). Many cancers, however, contain constitutively high levels of cytosolic p17 Survivin, and over-expression of this protein has been shown to block apoptosis both in vitro in cultured cells and in vivo in transgenic mice (Ambrosini, G. et al. 1997 Nature Med 3:917-921; Grossman, D. et al. 2001 J Invest 108:991-999; Reed, J. C. 2001 J Clin Invest 108:965-969). Antisense and dominant-negative experiments have provided proof of concept evidence suggesting that interfering with Survivin function could be a worthwhile strategy for promoting apoptosis of tumor cells (Reed, J. C. 2001 J Clin Invest 108:965-969; Li, F. et al. 1999 Nature Cell Biol 1:461-466; Mesri, M., et al. 2001 J Clin Invest 108:981-990). However, at present it is unclear how Survivin blocks apoptosis.
Survivin is a member of a family of proteins which all contain a characteristic zinc-binding fold called the BIR domain. Many of these BIR-containing proteins have been shown to suppress apoptosis when over-expressed, thus prompting the term Inhibitor of Apoptosis Proteins (IAPs). The principal mechanism of apoptosis suppression by IAP-family members such as XIAP has been defined. These proteins directly bind and potently suppress the activity of Caspases (Deveraux, Q. L. & Reed, J. C. 1999 Genes Dev 13:239-252), a group of intracellular proteases responsible for apoptosis (reviewed in Cryns, V. & Yuan, Y. 1999 Genes Dev 12:1551-1570). Though some studies have suggested that p17 Survivin also binds and suppresses Caspases, others have failed to demonstrate direct effects on these proteases (Shin, S. et al. 2001 Biochem 40:1117-1123; Verdecia, M. A. et al. 2000 Nature Struct Biol 7:602-608; Conway, E. M. et al. 2000 Blood 95:1435-1442; Banks, D. P. et al. 2000 Blood 96:4002-4003).
Because Survivin is over-expressed in the majority of tumors (Velculescu, V. E. et al. 1999 Nature Gen 23:387-388; Ambrosini, (G. et al. 1997 Nature Med 3:917-921), this protein has emerged as a promising target for development of new cancer therapies. However, progress in devising strategies for nullifying Survivin has been hampered by a lack of knowledge about its biochemical mechanism of action.
HBXIP was originally isolated as a human protein which binds the viral oncogenic protein, HBX, of the Hepatitis B Virus (HBV) (Melegari, M. et al. 1998 J Virol 72:1737-1743). HBXIP encodes a protein of 9.6-kDa with a putative leucine zipper motif. Expression of HBXIP mRNA has been demonstrated in essentially all tissues examined to date, and is not limited to the liver (Melegari, M. et al. 1998 J Virol 72:1737-1743). In the context of HBV-infection, HBXIP reportedly reduces viral replication and abolishes the transactivation function of viral HBX protein (Melegari, M. et al. 1998 J Virol 72:1737-1743), however, little is known about the physiological roles of HBXIP in human cells.
Thus, there is a need for investigation into the anti-apoptotic mechanism of Survivin and its role in neoplastic diseases as a means for developing novel cancer treatments.